Processes for preparing darifenacin hydrobromide

ABSTRACT

The invention encompasses processes for the preparation of darifenacin hydrobromide.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a division of U.S. patent application Ser. No. 11/646,919, which claims the benefit of priority to U.S. provisional application Ser. Nos. 60/754,395, filed Dec. 27, 2005; 60/772,250, filed Feb. 9, 2006; 60/776,311, filed Feb. 23, 2006; 60/809,147, filed May 25, 2006; 60/813,579, filed Jun. 8, 2006; 60/836,557, filed Aug. 8, 2006; 60/837,407, filed Aug. 10, 2006; 60/850,184, filed Oct. 5, 2006; 60/859,332, filed Nov. 15, 2006; and 60/873,680, filed Dec. 7, 2006, hereby incorporated by reference. This application is also related to U.S. application Ser. Nos. 11/647,109, filed Dec. 27, 2006 and entitled “Processes for Preparing Darifenacin Hydrobromide;” and 11/646,915, filed Dec. 27, 2006 and entitled “Pure Darifenacin Hydrobromide Substantially Free of Oxidized Darifenacin and Salts Thereof and Process for the Preparation Thereof,” hereby incorporated by reference.

FIELD OF THE INVENTION

The invention encompasses processes for the preparation of darifenacin hydrobromide.

BACKGROUND OF THE INVENTION

Darifenacin, (S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide, a compound having the chemical structure,

Darifenacin

is a selective M3 receptor antagonist. Blockade of destructor muscle activity manifests in an increase in urine volume that the bladder can retain, reduction of urination frequency, and decrease in pressure and urgency associated with the urge to urinate, and thereby episodes of incontinence are reduced.

Darifenacin is administered as the hydrobromide salt, (S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide hydrobromide, of the structure

Darifenacin Hydrobromide

and is marketed under the trade name ENABLEX® by Novartis.

U.S. Pat. No. 5,096,890, hereby incorporated by reference, discloses three routes for the synthesis of darifenacin hydrobromide; all of which comprise the cumbersome and hazardous Mitsunobu reaction, described in the following Scheme.

Accordingly, 1-tosyl-3-(R)-pyrrolidinol is reacted with methyl tosylate, and with diethylazodicarboxylate (DEAD), a very dangerous reagent. Typically, the product is contaminated with triphenylphosphine oxide, which is very difficult to separate from the desired product. Moreover, other toxic and hazardous reagents, such as pyridine and NaH, are used in other steps of the synthesis.

The process disclosed in U.S. publication No. 20003/0191176 for the preparation of Darifenacin hydrobromide requires the use of BF₃, which is also a toxic reagent.

Therefore, there is a need in the art for a process for the preparation of darifenacin hydrobromide that does not use toxic and dangerous reagents and that can be performed on an industrial scale. The present invention provides such processes.

SUMMARY OF THE INVENTION

In one embodiment, the invention encompasses an N-protected-3-(S)pyrrolidinol of the formula,

N-protected-3-(S)-pyrrolidinol

wherein X is S, SO₂, Si, or CO, and R is phenyl, tolyl, ortho, meta, or para-xylyl, linear or branched C₁₋₁₀ alkyl, H, or CF₃.

In another embodiment, the invention encompasses a process for preparing darifenacin hydrobromide comprising converting the N-protected-3-(S)-pyrrolidinol into darifenacin hydrobromide.

In another embodiment, the invention encompasses a process for preparing darifenacin hydrobromide comprising: a) combining 3-(S)-(+)-hydroxypyrrolidine, a solvent selected from the group consisting of a C₆₋₉ aromatic hydrocarbon, a polar aprotic organic solvent, and mixtures thereof, a sulfonyl halide, and a base to obtain 1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine of formula I,

b) reacting the 1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine of formula I with diphenylacetonitrile and an inorganic base in an organic solvent selected from the group consisting of a C₆₋₉ aromatic hydrocarbon, a polar aprotic organic solvent, and mixtures thereof to obtain (S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil)acetonitrile of formula II;

c) reacting the (S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil)acetonitrile intermediate of formula II with a bromine acceptor selected from the group consisting of phenol and naphthol and an acid to obtain (S)-2,2-diphenyl-2-(3-pyrrolidinil) acetonitrile salt of formula III,

wherein the bromine acceptor is phenol only when the acid is HBr; d) combining the (S)-2,2-diphenyl-2-(3-pyrrolidinil) acetonitrile salt of formula III and an inorganic base with a solvent selected from the group consisting of water immiscible organic solvent, a polar aprotic organic solvent, water, and mixtures thereof to form a mixture; e) acidifying the mixture; f) heating the mixture; g) basifying the mixture; h) combining the mixture with a C₁₋₄ alcohol and L-tartaric acid to obtain 3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate of formula VI;

i) reacting the 3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate of formula VI with a compound of the formula V

and a base in a solvent selected from the group consisting of a C₆₋₉ aromatic hydrocarbon, a polar organic solvent, water, and mixtures thereof; and j) admixing HBr with the mixture to obtain darifenacin bromide, wherein X is either C₁₋₁₀ alkyl or C₆₋₉ aryl Y is a leaving group selected from the group consisting of I, Cl, mesyloxy, Br, tosyloxy, trifluoroacetyloxy, and trifluoromethansulfonyloxy, and Z₁ is an acid.

In another embodiment, the invention encompasses a process for preparing 1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine of formula I

comprising combining 3-(S)-(+)-hydroxypyrrolidine, a sulfonyl halide, and a base in a solvent selected from the group consisting of a C₆₋₉ aromatic hydrocarbon, a polar aprotic organic solvent, and mixtures thereof to obtain 1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine, wherein X is either C₁₋₁₀ alkyl or C₆₋₉ aryl.

In another embodiment, the invention encompasses a process for preparing darifenacin hydrobromide comprising preparing 1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine and converting the 1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine into darifenacin hydrobromide.

In another embodiment, the invention encompasses a process for preparing (S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil) acetonitrile of formula II

comprising combining 1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine of formula I, diphenylacetonitrile, and an inorganic base in an organic solvent selected from the

group consisting of a C₆₋₉ aromatic hydrocarbon, a polar aprotic organic solvent, and mixtures thereof, and an inorganic base to obtain (S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil)acetonitrile, wherein X is either C₁₋₁₀ alkyl or C₆₋₉ aryl.

In another embodiment, the invention encompasses a process for preparing darifenacin hydrobromide comprising preparing (S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil)acetonitrile and converting the (S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil)acetonitrile into darifenacin hydrobromide.

In another embodiment, the invention encompasses a process for preparing 3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate comprising: a) combining (S)-2,2-diphenyl-2-(3-pyrrolidinil) acetonitrile salt of formula III,

a solvent selected from the group consisting of a water immiscible organic solvent, a polar aprotic organic solvent, water, and mixtures thereof, and an inorganic base to form a mixture; b) acidifying the mixture; c) heating the mixture; d) basifying the mixture; and e) combining the mixture with a C₁₋₄ alcohol and L-tartaric acid to obtain 3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate, wherein Z₁ is an acid.

In another embodiment, the invention encompasses a process for preparing darifenacin hydrobromide comprising preparing 3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate and converting the 3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate into darifenacin hydrobromide.

In another embodiment, the invention encompasses a compound of formula V

wherein Y is a leaving group selected from the group consisting of I, Cl, mesyloxy, Br, tosyloxy, trifluoroacetyloxy, and trifluoromethansulfonyloxy,

In another embodiment, the invention encompasses a process for preparing the compound of formula V;

comprising: a) combining 2(2,3-dihydrobenzofura-5-yl)-acetic acid, a C₁₋₄ alcohol, and a catalyst to obtain 2(2,3-dihydrobenzofura-5-yl)-acetic acid methyl ester; b) combining the 2(2,3-dihydrobenzofura-5-yl)-acetic acid methyl ester with a reducing agent and a C₄₋₆ alcohol to obtain 2(2,3-dihydrobenzofura-5-yl)-ethanol; and c) combining the 2(2,3-dihydrobenzofura-5-yl)-ethanol with a solvent selected from the group consisting of a C₁₋₂ halogenated hydrocarbon, C₃₋₆ ester, and C₆₋₉ aromatic hydrocarbon, and a substance containing a leaving group selected from the group consisting of Cl, mesyloxy, Br, tosyloxy, trifluoroacetyloxy, and trifluoromethansulfonyloxy, to obtain the compound of formula V, wherein Y is a leaving group selected from the group consisting of I, Cl, mesyloxy, Br, tosyloxy, trifluoroacetyloxy, and trifluoromethansulfonyloxy.

In another embodiment, the invention encompasses a process for preparing darifenacin hydrobromide comprising preparing the compound of formula V

and converting the compound of formula V into darifenacin hydrobromide, wherein Y is a leaving group selected from the group consisting of I, Cl, brosyloxy, Br, mesyloxy, tosyloxy, trifluoroacetyloxy, and trifluoromethansulfonyloxy.

In another embodiment, the invention encompasses a process for preparing a compound of the formula V,

comprising: a) combining the bisulfite complex of formula X,

water, NaOH, Na₂CO₃, a water immiscible hydrocarbon, and a reducing agent to form a mixture; and b) combining the mixture with a solvent selected from the group consisting of a C₁₋₂ halogenated hydrocarbon, C₃₋₆ ester, and C₆₋₉ aromatic hydrocarbon, a substance containing a leaving group selected from the group consisting of Cl, Br, mesyloxy, brosyloxy, tosyloxy, trifluoroacetyloxy, and trifluoromethansulfonyloxy to obtain the compound of formula V, wherein Y is a leaving group selected from the group consisting of I, Cl, brosyloxy, Br, mesyloxy, tosyloxy, trifluoroacetyloxy, and trifluoromethansulfonyloxy.

In another embodiment, the invention encompasses a process for preparing darifenacin hydrobromide comprising preparing the compound of formula V

and converting the compound of formula V into darifenacin hydrobromide, wherein Y is a leaving group selected from the group consisting of I, Cl, brosyloxy, Br, mesyloxy, tosyloxy, trifluoroacetyloxy, and trifluoromethansulfonyloxy.

In another embodiment, the invention encompasses a process for preparing darifenacin hydrobromide comprising: a) combining 3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate or the free base derivative of the following formula,

a derivative of ethyl-dihydrobenzofuran of the following formula V,

a solvent selected from the group consisting of a C₆₋₉ aromatic hydrocarbon, a polar organic solvent, water, and mixtures thereof, and a base to form a mixture; and b) admixing HBr with the mixture to obtain darifenacin hydrobromide.

DETAILED DESCRIPTION OF THE INVENTION

The invention encompasses an N-protected-3-(S)-pyrrolidinol of the formula,

N-protected-3-(S)-pyrrolidinol

wherein X is S, SO₂, Si, or CO, and R is phenyl, tolyl, ortho, meta, or para-xylyl, linear or branched C₁₋₁₀ alkyl, H, or CF₃. Preferably, X is SO₂. Preferably, R is tolyl.

In one preferred embodiment, X is S, and R is phenyl, such that the N-protected-3-(S)-pyrrolidinol corresponds to N-phenylthio-3-(S)-pyrrolidinol of the structure

N-phenylthio-3-(S)-pyrrolidinol

In another preferred embodiment, X is S, and R is tolyl, such that the N-protected-3-(S)-pyrrolidinol corresponds to N-Tolylthio-3-(S)-Pyrrolidinol of the structure

N-Tolylthio-3-(S)-Pyrrolidinol

The N-tolylthio-3-(S)-Pyrrolidinol may be characterized by a melting temperature of about 108° C. to about 112° C. When X is S, and R is xylyl, the N-protected-3-(S)pyrrolidinol corresponds to N-Xylylthio-3-(S)-pyrrolidinol of the structure

N-Xylylthio-3-(S)-pyrrolidinol

In another preferred embodiment, X is S, and R is linear or branched C₁₋₁₀ alkyl, such that the N-protected-3-(S)-pyrrolidinol corresponds to N-Alkylthio-3-(S)-Pyrrolidinol of the structure

Alkylthio-3-(S)-Pyrrolidinol

In another preferred embodiment, X is SO₂, and R is phenyl, such that the N-protected-3-(S)-pyrrolidinol corresponds to N-Benzensulfonyl-3-(S)-Pyrrolidinol of the structure

N-Benzensulfonyl-3-(S)-Pyrrolidinol

In another preferred embodiment, X is SO₂, and R is tolyl, such that the N-protected-3-(S)-pyrrolidinol corresponds to N-Tosyl-3-(S)-Pyrrolidinol of the structure

N-Tosyl-3-(S)-Pyrrolidinol

In another preferred embodiment, X is SO₂, and R is xylyl, such that the N-protected-3-(S)-pyrrolidinol corresponds to N-Xylylsulfonyl-3-(S)-Pyrrolidinol of the structure

N-Xylylsulfonyl-3-(S)-Pyrrolidinol

In another preferred embodiment, X is SO₂, and R is linear or branched C₁₋₁₀ alkyl, such that the N-protected-3-(S)-pyrrolidinol corresponds to N-Alkylsulfonyl-3-(S)-pyrrolidinol of the structure

N-Alkylsulfonyl-3-(S)-pyrrolidinol

In another preferred embodiment, X is Si, and R is linear or branched C₁₋₁₀ alkyl, such that the N-protected-3-(S)-pyrrolidinol corresponds to N-Alkylsilyl-3-(S)-pyrrolidinol of the structure

N-Alkylsilyl-3-(S)-pyrrolidinol

In another preferred embodiment, X is CO, and R is H, such that the N-protected-3-(S)-pyrrolidinol corresponds to N-Formyl-3-(S)-pyrrolidinol of the structure

N-Formyl-3-(S)-pyrrolidinol

In another preferred embodiment, X is CO, and R is CF₃, such that the 3-(S)-(+)hydroxypyrrolidine corresponds to N-protected-3-(S)-pyrrolidinol of the structure

N-Trifluoroacetyl-3-(S)-pyrrolidinol

In another preferred embodiment, X is CO, and R is CH₃, such that the N-protected-3-(S)-pyrrolidinol corresponds to N-Acetyl-3-(S)-pyrrolidinol of the structure

N-Acetyl-3-(S)-pyrrolidinol

The N-protected-3-(S)-pyrrolidinol may be converted into darifenacin hydrobromide.

Darifenacin Hydrobromide

The invention also encompasses a process for the preparation of darifenacin hydrobromide according to the following general scheme:

wherein X is either C₁₋₁₀ alkyl or C₆₋₉ aryl Y is a leaving group selected from the group consisting of I, Cl, mesyl, Br, tosyl, trifluoroacetyl, and trifluoromethansulfonyl, and Z is an acid. Preferably, X is a C₆₋₉ aryl, and more preferably tolyl. Preferably, Y is Cl. Preferably, Z is HBr or HCl. The process of the invention allows one to prepare darifenacin hydrobromide without the need to employ the cumbersome Mitsunobu reaction. In addition, the process can be practiced on an industrial scale with minimum production hazards.

The process comprises: combining 3-(S)-(+)-hydroxypyrrolidine, a solvent selected from the group consisting of a C₆₋₉ aromatic hydrocarbon, a polar aprotic organic solvent, and mixtures thereof, a sulfonyl halide, and a base to obtain the intermediate of formula I; reacting the intermediate of formula I with diphenylacetonitrile, and an inorganic base in an organic solvent selected from the group consisting of a C₆₋₉ aromatic hydrocarbon, a polar aprotic organic solvent, and mixtures thereof to obtain the intermediate of formula II; reacting the intermediate of formula II with a bromine acceptor selected from the group consisting of phenol and naphthol and an acid to obtain the intermediate of formula III, wherein the bromine acceptor is phenol only when the acid is HBr; combining the intermediate of formula III with an inorganic base in a solvent selected from the group consisting of water immiscible organic solvent, a polar aprotic organic solvent, water, and mixtures thereof, acidifying, heating, basifying, combining with a C₁₋₄ alcohol and L-tartaric acid to obtain the intermediate of formula VI; and reacting the intermediate of formula VI with a derivative of ethyl-dihydrobenzofuran of the formula V and a base in a solvent selected from the group consisting of a C₆₋₉ aromatic hydrocarbon, a polar organic solvent, water, and mixtures thereof, and adding HBr to obtain darifenacin bromide.

The N—O-sulfonation reaction of the present invention is performed using solvents that are not hazardous and toxic, as compared to the pyridine that is used in U.S. Pat. No. 5,096,890. Also, the reaction leads to a much higher yield (the process of the invention provides darifenacin hydrobromide in 96% yield, while U.S. Pat. No. 5,096,890 reports the preparation of darifenacin hydrobromide in 75% yield). Moreover, the product is isolated very easily from a mixture of toluene and water, as compared to the difficult isolation performed in U.S. Pat. No. 5,096,890, which includes recovering the product by time consuming steps, such as distillation of pyridine, extractions with dichloromethane, and crystallization from n-propanol. Hence, the sulfonation reaction limits the process from being scaled up.

The intermediate of formula I, 1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine

is prepared by a process comprising combining 3-(S)-(+)-hydroxypyrrolidine of the following formula,

3-(S)-(+)-hydroxypyrrolidine

a solvent selected from the group consisting of a C₆₋₉ aromatic hydrocarbon, a polar aprotic organic solvent, and mixtures thereof, a sulfonyl halide, and a base; wherein X is either C₁₋₁₀ alkyl or C₆₋₉ aryl. Preferably, X is C₆₋₉ aryl, and more preferably tolyl.

When X is tolyl, the compound of formula I refers to 1-tosyl-3-(S)-(−)-tosyloxypyrrolidine of the following formula.

Typically, the 1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine of formula I is obtained by the above process in a purity of about 95% to about 99% area by HPLC. The starting material, 3-(S)-(+)-hydroxypyrrolidine is commercially available.

Typically, combining the 3-(S)-(+)-hydroxypyrrolidine and the solvent provides a solution. The sulfonyl halide is then added to the solution to form a mixture. The addition of the sulfonyl halide to the solution leads to a rise in the temperature of the solution, typically to about 35° C. to about 40° C. Preferably, the base is then added to the mixture to form a reaction mixture, which leads to a second rise in temperature, typically to about 50° C. to about 60° C. Preferably, after the base is added, the reaction mixture is maintained at a temperature of about 25° C. to about reflux, more preferably, at about 50° C. to about 55° C. Preferably, after addition of the base, the reaction mixture is maintained for about 2 to about 10 hours, more preferably, for about 4 to about 6 hours.

Preferably, the C₆₋₉ aromatic hydrocarbon is toluene or o-, m-, or p-xylene. Preferably, the polar aprotic organic solvent is a C₁₋₁₀ halogenated aliphatic hydrocarbon, amide, or sulfoxide. A preferred C₁₋₁₀ halogenated aliphatic hydrocarbon is C₁₋₅ halogenated hydrocarbon, more preferably, dichloromethane (referred to as DCM), 1,2-dichloroethane or dichloropentane. Preferably, the amide is C₁₋₂ amide, more preferably, either dimethylformamide (referred to as DMF) or dimethylacetamide (referred to as DMA). Preferably, the sulfoxide is C₁₋₄sulfoxide, more preferably, dimethylsulfoxide (referred to as DMSO). The more preferred solvent is toluene.

Optionally, a phase transfer catalyst (referred to as PTC) may be used to increase the reaction rate. When the solvent is a C₆₋₉ aromatic hydrocarbon, preferably, a phase transfer catalyst is used. Preferably, the PTC is added to the solution of 3-(S)-(+)-hydroxypyrrolidine prior to the addition of the sulfonyl halide. Preferably, the PTC is selected from the group consisting of tetrabutylammonium bromide, ALIQUAT® tributylmethylammonium chloride, tetrabutylammonium sulfate, and DMSO, and more preferably tetrabutylammonium bromide.

Preferably, the halide moiety of the sulfonyl halide is selected from chloride, bromide, and iodide, and more preferably chloride. Preferably, the sulfonyl halide is tosylchloride, mesylchloride, or brosylchloride, and more preferably tosylchloride. Preferably, the sulfonyl halide is added portion-wise.

Preferably, the base is either an inorganic base or an organic base. A preferred organic base is selected from the group consisting of aliphatic and aromatic amines. Preferably, the aliphatic amine is triethylamine, methylmorpholine, or N,N-diisopropylethyl amine. A preferred aromatic amine is pyridine. The inorganic base is added, preferably, in a form of an aqueous solution. The aqueous solution contains, preferably, an alkali base, and more preferably either sodium hydroxide or potassium hydroxide. Preferably, the base is added slowly, more preferably over about a half an hour to about two hours, and even more preferably over about one hour.

The process for preparing 1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine of formula I may further comprise a recovery step. The 1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine may be recovered by any method known to one of ordinary skill in the art. Such methods include, but are not limited to, adding water to the reaction mixture; cooling the reaction mixture to obtain a precipitate of the 1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine, and filtering the precipitate from the reaction mixture. Preferably, the addition of water provides a suspension. Preferably, the suspension is cooled to a temperature of about 20° C. to about −5° C., and more preferably to about 5° C. to about 0° C., to induce precipitation of the 1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine. Preferably, the cooled suspension is maintained for at least about one hour, preferably, for about 1 to about 2 hours, to give a precipitate of 1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine. The precipitate is then filtered and dried.

The 1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine of formula I thus obtained may then be converted to darifenacin bromide.

The intermediate of formula II, (S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil)acetonitrile

is prepared by a process comprising combining 1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine of formula I, diphenylacetonitrile, an organic solvent selected from the group consisting of a C₆₋₉ aromatic hydrocarbon, a polar aprotic organic solvent, and mixtures thereof, and an inorganic base; wherein X is either C₁₋₁₀ alkyl or C₆₋₉ aryl. Preferably, X is C₆₋₉ aryl, and more preferably tolyl.

When X is tolyl, the compound of formula II refers to (S)-2,2-diphenyl-2-(1-tosyl-3-pyrrolidinil)acetonitrile of the following formula.

(S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil)acetonitrile of the formula II is obtained by the above process in a purity of about 95% to about 99% area by HPLC, and more preferably about 99% to about 100% area by HPLC.

Typically, combining the diphenylacetonitrile and the organic solvent provides a first mixture. The addition of the inorganic base to the first mixture typically causes the temperature of the first mixture to rise to about 20° C. to about 40° C., and preferably to about 25° C. to about 35° C. Preferably, the first mixture is cooled to a temperature of about 30° C. to about 15° C., and more preferably to a temperature of about 25° C. to about 15° C., prior to the addition of the 1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine of formula I. Typically, the addition of the 1-X-sulfonyl-3-(S)-(−)-X-sulfonyloxypyrrolidine of formula I provides a second mixture. Preferably, the second mixture is heated to a temperature of about 50° C. to about 100° C., and more preferably to a temperature of about 70° C. to about 75° C. The heated second mixture is maintained, preferably, for about 3 to about 6 hours, and more preferably, for about 4 to about 5 hours.

Preferably, the C₆₋₉ aromatic hydrocarbon is toluene. Preferably, the polar aprotic organic solvent is either amide or sulfoxide. A preferred amide is C₁₋₂ amide, more preferably, either DMF or DMA. A preferred sulfoxide is C₁₋₄ sulfoxide, more preferably, DMSO. The more preferred organic solvent is DMF.

Preferably, the inorganic base is either a metal alkoxide or an alkali hydroxide. A preferred metal alkoxide is either sodium tert-butoxide or sodium methoxide. A preferred alkali hydroxide is either sodium or potassium hydroxide. The more preferred inorganic base is a metal alkoxide, most preferably either sodium or potassium tert-butoxide.

The process for preparing (S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil)acetonitrile of formula II may further comprise a recovery step. The (S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil)acetonitrile of formula II may be recovered by adding to the second mixture to a mixture of water and a solvent selected from the group consisting of toluene, DCM, ethyl acetate (referred to as EtOAc), butyl acetate (referred to as BuOAc), and n-butanol to form a mixture having an aqueous and an organic phase; separating the aqueous and organic phases; washing the organic phase with water; and concentrating the organic phase under reduced pressure to obtain a concentrated residue. The residue is then cooled to a temperature of about 10° C. to about −10° C., and preferably to about 3° C. to about −3° C., to give a precipitate of (S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil)acetonitrile.

The (S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil)acetonitrile of formula II thus obtained may then be converted to darifenacin bromide, for example, by the process disclosed in Example 1 of U.S. Pat. No. 5,096,890 (reproduced below as Comparative Example 23).

The intermediate of formula III, (S)-2,2-diphenyl-2-(3-pyrrolidinil)acetonitrile salt, is prepared by a process comprising heating a mixture comprising the compound of formula II, a bromine acceptor selected from phenol and naphthol and an acid, wherein the bromine acceptor is phenol only when the acid is HBr. Preferably, the mixture is heated to a temperature of about 80° C. to about 120° C., more preferably, to about 117° C. to about 120° C. Preferably, the heated mixture is maintained for about 1 hour to about 2 hours, more preferably, for about 1 hour to about 1.5 hours. Preferably, the acid is selected from a group consisting of: phosphoric acid, perchloric acid, tribromomethanesulfonic acid, and HBr, more preferably, HBr. When using HBr as the acid, it is added in a form of an aqueous solution, having a concentration of about 30% to about 60%, more preferably, of about 48% to about 60%.

The (S)-2,2-diphenyl-2-(3-pyrrolidinil)acetonitrile salt of formula III may be recovered by a process comprising cooling the mixture to a temperature of about 30° C. to about 15° C., more preferably, to a temperature of about 30° C. to about 25° C., followed by extracting with a C₁₋₁₀ halogenated aliphatic hydrocarbon, and washing with brine. The organic phase is then concentrated under reduce pressure to give a residue containing the compound of formula III and the solvent. Preferably, the C₁₋₁₀ halogenated aliphatic hydrocarbon is C₁₋₅ halogenated hydrocarbon, more preferably, C₁₋₃ halogenated hydrocarbon. Most preferably, the C₁₋₃ halogenated hydrocarbon is selected from the group consisting of DCM, chloroform, dichloroethane, 1,1-dichloroethane, and 1,5-dichloropentane.

The residue is then combined with a second solvent selected from the group consisting of BuOAc, toluene, acetone, 2-butanone, and diisopropylether, followed by a complete removal of the C₁₋₁₀ halogenated aliphatic hydrocarbon, preferably, by distillation, to give a second residue.

The second residue, containing the compound of formula III and a solvent selected form the group consisting of BuOAc, toluene, acetone, 2-butanone, and diisopropylether can be purified by a crystallization process from a solvent selected from the group consisting of C₁₋₁₀ ester, C₁₋₁₀ ketone, C₁₋₁₀ ether, C₁₋₁₀ aliphatic hydrocarbon, C₆₋₉ aromatic hydrocarbon, and mixtures thereof.

Preferably, the C₁₋₁₀ ester is ethylacetate, n-butylacetate, i-butylacetate, or n-propylacetate, more preferably, ethylacetate. Preferably, the C₁₋₁₀ ketone is acetone, 2-butanone, methyl-isobutylketone, or cyclohexanone. A preferred C₁₋₁₀ ether is diethylether, diisopropylether, dibutylether, or methyl isobutylether. Preferably, the C₁₋₁₀ aliphatic hydrocarbon is pentane, hexanes, heptanes, or petroleum ether. Preferably, the C₆₋₉ aromatic hydrocarbon is toluene or xylenes. Preferably, a mixture of ethyl acetate (EtOAc) and hexane is used.

The intermediate 3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate of the formula VI,

is prepared by a process comprising combining (S)-2,2-diphenyl-2-(3-pyrrolidinil) acetonitrile salt of formula III,

a solvent selected from the group consisting of water immiscible organic solvent, a polar aprotic organic solvent, water, and mixtures thereof, and an inorganic base to obtain a mixture; acidifying the mixture; heating the mixture; basifying the mixture; and combining the mixture with a C₁₋₄ alcohol and L-tartaric acid; wherein Z₁ is an acid. Preferably Z₁ is either HBr or HCl.

Optionally, the free base of the following formula

may be used as a starting material. The free base of formula XI may be obtained by combining (S)-2,2-diphenyl-2-(3-pyrrolidinil)acetonitrile salt of formula III a solvent selected from the group consisting of water immiscible organic solvent, a polar aprotic organic solvent, water, and mixtures thereof, and an inorganic base.

Preferably, the water immiscible organic solvent is either a C₆₋₉ aromatic hydrocarbon or a C₁₋₁₀ halogenated aliphatic hydrocarbon. Preferably, the C₆₋₉ aromatic hydrocarbon is toluene, xylenes, i-propylbenzene or styrene, more preferably, toluene. A preferred C₁₋₁₀ halogenated aliphatic hydrocarbon is DCM, 2-dichloroethane, 1,1-dichloroethane, or 1,5-dichloropentane.

Preferably, the polar aprotic organic solvent is an ester, more preferably, EtOAc. The more preferred solvent is a mixture of C₁₋₁₀ halogenated aliphatic hydrocarbon and water, and most preferably, of DCM and water.

Preferably, the inorganic base is an aqueous solution of an alkali base. A preferred alkali base is an alkali hydroxide, an alkali carbonate, or an alkali bicarbonate. Preferably, the alkali hydroxide is either sodium hydroxide or potassium hydroxide. Preferably, the alkali carbonate is either sodium carbonate or potassium carbonate. A preferred alkali bicarbonate is either sodium bicarbonate or potassium bicarbonate. The more preferred base is alkali hydroxide, most preferably, sodium hydroxide.

Typically, the acidifying comprises adding an acid to the mixture and heating. Preferably, the mixture is heated to a temperature of about 80° C. to about 110° C., and more preferably to a temperature of about 90° C. to about 100° C. The mixture is maintained, preferably, for about 15 to about 20 hours, and more preferably, for about 16 to about 18 hours.

After maintaining, the mixture is basified, preferably, to a pH of about 10 to about 13 and more preferably, to a pH of about 11 to about 12. Preferably, the mixture is basified by adding an inorganic base. The addition of the base creates a foam, which is then dissolved in the C₁₋₄ alcohol and mixed with the L-tartaric acid to provide 3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate of the formula VI.

Preferably, the acid is a strong acid, more preferably a strong mineral acid, and even more preferably either sulfuric acid or phosphoric acid. Most preferably, the acid is sulfuric acid. Preferably, the concentration of the acid is of about 75% to about 90%, more preferably, about 80% to about 85%.

The foam may be recovered by cooling the reaction mixture to a temperature of about 30° C. to about 15° C., more preferably, to about 25° C. to about 20° C., followed by increasing the pH to obtain a mixture having an aqueous phase and an organic phase. The phases are separated and the aqueous phase is then extracted with a solvent selected from the group consisting of DCM, EtOAc, and toluene, followed by washing the resulting combined organic phases with water, and evaporating the solvent.

Preferably, the C₁₋₄ alcohol is methanol, ethanol, isopropanol, or n-butanol, more preferably ethanol, and most preferably 96% ethanol.

The process for preparing 3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate of formula VI may further comprise a recovery step. The 3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate of formula VI may be recovered by cooling the solution to a temperature of about 5° C. to about −5° C., preferably, to about 3° C. to about −3° C., to induce precipitation of the 3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate, followed by filtering the precipitated 3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate from the solution.

The 3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate of formula VI thus obtained may then be converted to darifenacin bromide.

According to the process of the invention, 3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate of formula VI is reacted with derivatives of ethyl-dihydrobenzofuran of the formula V to obtain darifenacin hydrobromide.

The invention encompasses a compound of formula V;

wherein Y is a leaving group selected from the group consisting of I, Cl, brosyloxy, Br, mesyloxy, tosyloxy, trifluoroacetyloxy, and trifluoromethansulfonyloxy. Preferably, Y is Cl. When Y is Cl, the compound of formula V corresponds to 5-(2-chloroethyl)-2,3-dihydrobenzo[2,3-b]furan of the following formula.

The derivatives of ethyl-dihydrobenzofuran of the formula V;

are prepared by a process comprising reacting 2(2,3-dihydrobenzofura-5-yl)-acetic acid of the formula,

a C₁₋₄ alcohol, and a catalyst to obtain 2(2,3-dihydrobenzofura-5-yl)-acetic acid methyl ester of the formula

combining the 2(2,3-dihydrobenzofura-5-yl)-acetic acid methyl ester with a reducing agent, in a C₄₋₆ alcohol to obtain 2(2,3-dihydrobenzofura-5-yl)-ethanol of the formula

and combining the 2(2,3-dihydrobenzofura-5-yl)-ethanol, a solvent selected from the group consisting of a C₁₋₂ halogenated hydrocarbon, C₃₋₆ ester, and C₆₋₉ aromatic hydrocarbon, and a substance containing a leaving group selected from the group consisting of Cl, Br, mesyloxy, brosyloxy, tosyloxy, trifluoroacetyloxy, and trifluoromethansulfonyloxy to obtain the compound of formula V; wherein Y is a leaving group selected from the group consisting of I, Cl, brosyl, Br, mesyl, tosyl, trifluoroacetyl, and trifluoromethansulfonyl. Preferably Y is Cl.

The starting 2(2,3-dihydrobenzofura-5-yl)-acetic acid is commercially available.

Preferably, the C₁₋₄ alcohol is selected from the group consisting of methanol, ethanol, propanol, and butanol, and more preferably methanol. Optionally, a mixture of solvents may be used. Preferably, the mixture is that of C₁₋₄ alcohol and toluene, and more preferably of methanol and toluene.

Preferably, the catalyst is an acid. Preferably, the acid is either an organic or an inorganic acid selected from the group consisting of sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, HCl, HClO₄, and H₃PO₄. More preferably, the acid is an inorganic acid, and even more preferably a mineral acid, and most preferably sulfuric acid.

The reaction between the 2(2,3-dihydrobenzofura-5-yl)-acetic acid, the C₁₋₄ alcohol and the catalyst may be performed, preferably, with heating. Preferably, the heating is done to a temperature of about 60° C. to about 70° C., and more preferably about 65° C. to about 70° C. Preferably, heating is done for about 1 to about 5 hours, and more preferably for about 2 to about 3 hours.

The process for preparing the 2(2,3-dihydrobenzofura-5-yl)-acetic acid methylester may further comprise a recovery step. The 2(2,3-dihydrobenzofura-5-yl)-acetic acid methylester may be recovered by a method known to one of ordinary skill in the art. Preferably, the 2(2,3-dihydrobenzofura-5-yl)-acetic acid methylester is recovered by adding a base to the reaction mixture comprising 2(2,3-dihydrobenzofura-5-yl)-acetic acid methylester; removing the solvent; adding a C₆₋₉ aromatic hydrocarbon; washing with a basic solution; and removing the solvent. Preferably, the base is sodium bicarbonate. Preferably, removing the solvent from the reaction mixture provides a residue. Preferably, the addition of a C₆₋₉ aromatic hydrocarbon to the residue provides a solution. Preferably, the C₆₋₉ aromatic hydrocarbon is toluene. Preferably, the basic solution is sodium bicarbonate.

Preferably, the C₄₋₆ alcohol is t-butanol. Preferably, a mixture of C₁₋₄ alcohol and C₄₋₆ alcohol is used, instead of the C₄₋₆ alcohol alone. More preferably, the mixture is that of methanol and t-butanol.

Preferably, the reducing agent is a metal hydride. Preferably, the metal hydride is selected from the group consisting of NaBH₄, LiAlH₄, and VITRIDE® sodium dihydro-bis-(2-methoxyethoxy) aluminate. More preferably, the reducing agent is NaBH₄.

Combining the 2(2,3-dihydrobenzofura-5-yl)-acetic acid methylester, the reducing agent, and the C₄₋₆ alcohol provides a suspension. Preferably, the suspension is heated to a temperature of about 65° C. to about 75° C., more preferably, of about 70° C. to about 75° C. Preferably, the C₁₋₄ alcohol is added drop-wise. Preferably, the drop-wise addition is done over a period of about 2 to about 6 hours, and more preferably over a period of about 5 to about 6 hours. Typically, adding the C₁₋₄ alcohol provides a mixture. Preferably, the mixture is maintained for a total time of about 5 to about 10 hours, and more preferably for about 5 to about 7 hours. If the reaction is not completed after 5 to about 10 hours, a second amount of a reducing agent can be added. Preferably, the reducing agent is added with a C₁₋₄ alcohol. After the addition of the reducing agent and a C₁₋₄ alcohol, the reaction is further maintained, preferably, for about 1 to about 14 hours, more preferably, for about 2 to about 3 hours.

The process for preparing the 2(2,3-dihydrobenzofura-5-yl)-ethanol may further comprise a recovery step. The 2(2,3-dihydrobenzofura-5-yl)-ethanol may be recovered by any method known to one of ordinary skill in the art. Preferably, the 2(2,3-dihydrobenzofura-5-yl)-ethanol is recovered by removing the solvent; adding water and a solvent selected from the group consisting of toluene, dichloromethane, and ethyl acetate to obtain a mixture having an aqueous phase and an organic phase; separating the aqueous and organic phases; extracting the organic phase with water and a solvent selected from the group consisting of toluene, dichloromethane, and ethyl acetate; extracting the organic phase with water; and removing the solvent. Preferably, the C₁₋₂ halogenated hydrocarbon is dichloromethane. A preferred C₃₋₆ ester is ethyl acetate, isopropylacetate, butylacetate, or isobutylacetate. Preferably, the C₆₋₉ aromatic hydrocarbon is toluene, xylenes, i-propylbenzene, or styrene. The preferred solvent is toluene.

Preferably, the substance containing a leaving group is selected from the group consisting of SOCl₂, PCl₃, PCl₅, POCl₃, tosylchloride, mesylchloride, brosylchloride, trifluoroacetyl chloride, and trifluoromethansulfonyl chloride. Preferably, the substance containing a leaving group is SOCl₂, PCl₃, PCl₅, or POCl₃, more preferably, SOCl₂. Preferably, the substance containing a leaving group is added drop-wise. When the substance containing a leaving group is one of tosylchloride, mesylchloride, brosylchloride, trifluoroacetyl chloride, and trifluoromethansulfonyl chloride, a base may also be used. Preferably, the base is either an organic or an inorganic base. The organic base may be, preferably, an aliphatic or aromatic amine. Preferably, the aliphatic amine is triethylamine, ethyldiisopropylamine, or N-methylmorpholine. A preferred aromatic amine is pyridine. The inorganic base is preferably either an alkali metal hydroxide or an alkali metal carbonate. Preferably, the alkali metal hydroxide is sodium hydroxide, potassium hydroxide, or cesium hydroxide. A preferred alkali metal carbonate is sodium, potassium, or cesium carbonate. The more preferred base is an organic base, preferably, triethylamine.

Preferably, combining the 2(2,3-dihydrobenzofura-5-yl)-ethanol with a solvent selected from the group consisting of a C₁₋₂ halogenated hydrocarbon, C₃₋₆ ester, and C₆₋₉ aromatic hydrocarbon, a substance containing a leaving group provides a mixture. Preferably, the mixture is heated to a temperature of about 60° C. to about 80° C., more preferably, of about 60° C. to about 70° C. The mixture is, preferably, maintained, for about 12 to about 20 hours, more preferably, for about 15 to about 18 hours.

The process for preparing the derivative of ethyl-dihydrobenzofuran of the formula V may further comprise a recovery step. The derivative of ethyl-dihydrobenzofuran of the formula V may be recovered by any method known to one of ordinary skill in the art. Preferably, the derivative of ethyl-dihydrobenzofuran of the formula V is recovered by cooling the reaction mixture to a temperature of about 30° C. to about 15° C., preferably, to about 25° C. to about 20° C., followed by adding the reaction mixture to a basic solution to form a mixture having an aqueous phase and an organic phase; separating the aqueous and organic phases; extracting the aqueous phase with toluene; washing the organic phase with water; removing the solvent; and decolorizing the obtained residue. Preferably, the basic solution is of sodium bicarbonate. Decolorization may be done by any method known to one of ordinary skill in the art, such as using activated charcoal.

The recovered derivative of ethyl-dihydrobenzofuran of formula V may be purified by crystallization from methanol/water or methanol/water/acetone. The process comprises dissolving the derivative of ethyl-dihydrobenzofuran of formula V in methanol, and adding water or a mixture of water and acetone, followed by maintaining for about an hour to about 3 hours to promote crystallization of the derivative of ethyl-dihydrobenzofuran of formula V. The crystallized derivative of ethyl-dihydrobenzofuran of formula V is then filtered, washed and dried.

Preferably, when the starting commercially available acid analogue 2,3-dihydrobenzofuran-5-acetic acid

has less than 0.4% area by HPLC of 5-benzofuranacetic acid, the obtained

5-(2-hydroxyethyl)-2,3-dihydrobenzofuran of formula III

has less than 0.5% of 2-(benzofuran-5-yl)ethanol of following formula.

Preferably, the use of the compound of formula III having less than 0.5% area by HPLC of 2-(benzofuran-5-yl)ethanol in a combination with an aromatic hydrocarbon, more preferably, C₆₋₉ aromatic hydrocarbon, most preferably toluene, as a solvent, provides ethyl-dihydrobenzofuran of formula V having less than 0.25% ethyl-benzofuran of the following formula,

as exemplified in Examples 21 and 22 below.

Alternatively, the derivatives of ethyl-dihydrobenzofuran of the formula V,

are prepared by a process comprising combining a bisulfite complex of formula X,

water, NaOH, Na₂CO₃, a water immiscible hydrocarbon, and a reducing agent to form a mixture comprising of 2(2,3-dihydrobenzofura-5-yl)-ethanol; and combining the mixture comprising of 2(2,3-dihydrobenzofura-5-yl)-ethanol with a solvent selected from the group consisting of C₁₋₂ halogenated hydrocarbons, C₃₋₆ esters, and C₆₋₉ aromatic hydrocarbons and a substance containing a leaving group selected from the group consisting of Cl, Br, mesyloxy, brosyloxy, tosyloxy, trifluoroacetyloxy, and trifluoromethansulfonyloxy to obtain the compound of formula V, wherein Y is a leaving group selected from the group consisting of I, Cl, brosyl, Br, mesyl, tosyl, trifluoroacetyl, and trifluoromethansulfonyl. Preferably, Y is Cl.

The starting compound of formula X may be prepared by combining 2-(2,3-dihydrobenzofuran-5-yl)acetaldehyde, a water immiscible hydrocarbon, and Na₂S₂O₅ to form a mixture of the compound of formula X. Preferably, the water immiscible hydrocarbon is either a C₆₋₉ aromatic hydrocarbon or a saturated hydrocarbon. Preferably, the saturated hydrocarbons are C₅₋₁₀ saturated hydrocarbons, more preferably, pentane, hexanes or heptanes. Preferably, the C₆₋₉ aromatic hydrocarbon is toluene, xylenes, i-propylbenzene, or styrene. The more preferred solvent is toluene. Na₂S₂O₅ may be used in a solid form or in a form of an aqueous solution. Preferably, Na₂S₂O₅ is used in a form of an aqueous solution. Preferably, after the addition of Na₂S₂O₅ the mixture obtained is maintained at a temperature of about 15° C. to about 35° C., more preferably, at about 20° C. to about 25° C. Preferably, the mixture is maintained for about 2 hours to about 4 hours to obtain the compound of formula X. Preferably, NaOH is added to a suspension of the compound of formula X in water to obtain a basic mixture comprising 2-(2,3-dihydrobenzofuran-5-yl)acetaldehyde. Preferably, the pH of the basic mixture is about 9 to about 11, more preferably about 9.5 to about 10.5, and even more preferably about 10 to about 10.2.

Preferably, after adjusting the pH, Na₂CO₃ and a water immiscible hydrocarbon are added to obtain a mixture. Preferably, the water immiscible hydrocarbon is either a C₆₋₉ aromatic hydrocarbon or a saturated hydrocarbon. Preferably, the C₆₋₉ aromatic hydrocarbon is toluene. Preferably, the saturated hydrocarbons are C₅₋₁₀ saturated hydrocarbons. A preferred saturated hydrocarbon is either heptane or cyclohexane. The more preferred solvent is toluene, xylenes, i-propylbenzene, or styrene.

Preferably, the mixture is cooled to a temperature of about 20° C. to about 0° C., more preferably to about 110° C. to about 5° C., prior to the addition of the reducing agent. Preferably, adding a reducing agent provides a reaction mixture. Preferably, the reducing agent is selected from the group consisting of NaBH₄, LiAlH₄, and H₂/Pd. A solution or solid NaBH₄ may be used. Preferably, a solution of NaBH₄ is used. Preferably, the NaBH₄ is in solution in water or an alcohol. Preferably, the alcohol is a C₃₋₆ alcohol, propanol, i-propanol, butanol, i-butanol, amylalcohol, or cyclohexanol. The more preferred solvent is water.

Preferably, the solution of the reducing agent is added drop-wise. Preferably, the drop-wise addition is done over a period of about 0.5 hour to about 1.5 hours, and more preferably over about 45 to about 60 minutes.

Preferably, a pH of about 9 to about 11, more preferably, about 9.8 to about 10.2 is maintained during the addition.

Preferably, after the addition of the reducing agent, the temperature is raised to about 10° C. to about 25° C., more preferably, to about 15° C. to about 25° C. Preferably, after raising the temperature, the reaction mixture is maintained for about 0.5 hour to about 1.5 hours, more preferably, for about 1 hour, to obtain the 2(2,3-dihydrobenzofura-5-yl)-ethanol.

Preferably, combining the 2(2,3-dihydrobenzofura-5-yl)-ethanol with a solvent selected from the group consisting of a C₁₋₂ halogenated hydrocarbon, C₃₋₆ ester, and C₆₋₉ aromatic hydrocarbon, and a substance containing a leaving group provides a mixture. Preferably, the mixture is heated to a temperature of about 60° C. to about 80° C., more preferably, of about 60° C. to about 70° C. The mixture is, preferably, maintained, for about 12 to about 20 hours, more preferably, for about 15 to about 18 hours. Preferably, the heated mixture provides ethyl-dihydrobenzofuran of the formula V.

The derivative of ethyl-dihydrobenzofuran of formula V may then be converted to darifenacin bromide.

Darifenacin hydrobromide is prepared from the 3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate of formula VI by a process comprising combining 3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate of formula VI or the free base derivative of the formula XI,

a derivative of ethyl-dihydrobenzofuran of the formula V, a solvent selected from the group consisting of a C₆₋₉ aromatic hydrocarbon, a polar organic solvent, water, and mixtures thereof, and a base to form a mixture; and admixing HBr with the mixture to obtain darifenacin hydrobromide, wherein Y is a leaving group selected from the group consisting of I, Cl, brosyl, Br, mesyloxy, tosyloxy, trifluoroacetyloxy, and trifluoromethansulfonyloxy.

The free base derivative of 3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate may be obtained by the process described above for the preparation of compound of formula VI, excluding the last step, wherein C₁₋₄ alcohol and L-tartaric acid are added.

Preferably, the polar aprotic organic solvent is selected from the group consisting of an amide, a C₁₋₁₀ halogenated aliphatic hydrocarbon, a sulfoxide, an ester, a nitrile, and a ketone. A preferred amide is DMF. A preferred C₁₋₁₀ halogenated aliphatic hydrocarbon is C₁₋₅ halogenated aliphatic hydrocarbon, more preferably, DCM. Preferably, the sulfoxide is C₂₋₅ sulfoxide, more preferably, DMSO. Preferably, the ester is C₂₋₅ ester, more preferably, EtOAc. A preferred ketone is C₃₋₆ ketone, more preferably, MEK Preferably, the nitrile is C₂₋₄ nitrile, more preferably, ACN. Preferably, the C₆₋₉ aromatic hydrocarbon is C₆₋₉ aromatic hydrocarbon, more preferably, toluene. Preferred mixtures are either that of toluene and water or that of DCM and water. The more preferred solvent is water.

The base may be an inorganic base or an organic base. A preferred organic base is selected from the group consisting of aliphatic and aromatic amines. Preferably, the aliphatic amine is triethylamine, tribytulamine, methylmorpholine, or N,N-diisopropylethyl amine. Preferably, the aromatic amine is pyridine. A preferred inorganic base is either alkali carbonate or alkali bicarbonate. Preferably, the alkali carbonate is sodium carbonate or potassium carbonate. Preferably, the alkali bicarbonate is either sodium bicarbonate or potassium bicarbonate. The most preferred base is an alkali carbonate, even most preferably, potassium carbonate.

Preferably, the mixture is heated to a temperature of about 50° C. to about reflux, and more preferably to a temperature of about 60° C. to about reflux, prior to admixing with HBr. Preferably, the mixture is maintained, under heating, for about 1 to about 5 hours, and more preferably for about 2 to about 3 hours. After maintaining the mixture, the mixture is cooled to a temperature of 35° C. to about 15° C., and preferably to about 25° C. to about 15° C. Preferably, after cooling, an organic solvent selected from the group consisting of DCM, EtOAc, and butyl acetate is added to the mixture, to give a mixture having an aqueous phase and an organic phase. The phases are then separated, and HBr is admixed with the organic phase. Preferably, HBr is added to the organic phase.

Preferably, a small amount of an anhydride may be added to the organic phase, after separating the phases, followed by maintaining for about 1 to about 3 hours. After maintaining, the organic solvent is removed, and a C₂₋₅ alcohol and hydrobromic acid are added, to obtain darifenacin hydrobromide. Preferably, the C₂₋₅ alcohol is n-butanol, sec-butanol, ethanol, 2-methyl-2-butanol, or isopropanol, more preferably, n-butanol.

Darifenacin hydrobromide may be recovered by removing the residual water and the organic solvent from the acidic mixture obtained after the addition of HBr, preferably, by distillation under vacuum, to induce precipitation of the darifenacin hydrobromide. The mixture is then cooled to room temperature and the resulting precipitate of darifenacin hydrobromide is separated from the mixture by filtration.

Darifenacin hydrobromide may be further purified by crystallizing the recovered precipitate from a C₂₋₅ alcohol. The process comprises suspending the precipitate in a C₂₋₅ alcohol, heating the suspension to a temperature sufficient to induce dissolution of the darifenacin hydrobromide, and cooling the resulting solution to induce crystallization of the darifenacin hydrobromide. Prior to cooling, the solution may be purified with active charcoal. The crystallized product may be isolated by filtration, washing and drying. Preferably, the C₂₋₅ alcohol is n-butanol, sec-butanol, ethanol, 2-methyl-2-butanol, or isopropanol, and more preferably n-butanol.

The obtained darifenacin hydrobromide may have a purity of about 99% to about 100% area by HPLC, preferably about 99.6%-99.85% area by HPLC, and more preferably about 99.7% to about 99.8% area by HPLC.

Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one of ordinary skill in the art from consideration of the specification. The invention is further defined by reference to the following examples. It will be apparent to those of ordinary skill in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.

EXAMPLES

HPLC Column & GEMINI C18 110A 250 mm × 4.6 mm × 5.0 μm Packing: (cat. No. 00G-4435-E0) from Phenomenex (or equivalent) Buffer: K₂HPO₄ 0.02 M pH 7.0: 3.48 g of K₂HPO₄ in 1000 ml of deionized water, adjust pH at 7.0 ± 0.2 with H₃PO₄ 15% (w/v). Filter on a 0.45 μm filter. Eluent A: Acetonitrile Time (min) % Buffer % Eluent A Gradient:  0 50 50 20 30 70 30 30 70 Equilibrium time: 8 minutes Sample volume: 5.0 μl Flow Rate: 1.0 ml/min Detector: UV at 215 nm Column 35° C. temperature: Diluent: H₂O:Acetonitrile (50:50)

Example 1 Preparation of 1-tosyl-3-(S)-(−)tosyloxyppyrrolidine (Formula I)

(S)-3-pyrrolidinol (30 g, 0.344 moles) was dissolved in toluene (150 ml) and tetrabutylammonium bromide (3.39 g, 0.0105 moles) was added to the solution. p-Toluensulfonylchloride (140.94 g, 0.7393 moles) was then added portion-wise to the solution, causing the temperature of the solution to rise to 35 to 40° C. Then, 30% NaOH (112.1 g, 0.8407 moles) was slowly added to the solution over about 1 hour, causing the temperature of the solution to rise to 55 to 60° C. After maintaining the solution for 5 hours at 55-60° C., the reaction was complete. Water (30 ml) was then added, and the resulting suspension was cooled to 0° C. over 1 hour to give a solid. The solid was filtered and washed with cold toluene and water to give the title compound. (Dry weight 127.95 g, yield 94%, HPLC purity 99.2% area). The main impurity is 1-tosyl-3-(S)-pyrrolidinol (reaction intermediate) in an amount of 0.05% area by HPLC.

Example 2 Preparation of (S)-2,2-diphenyl-2-(1-tosyl-3-pyrrolidinil)acetonitrile (Formula II)

Diphenylacetonitrile (63.7 g, 0.3296 moles) was dissolved in DMF (395 ml), followed by adding sodium tert-butylate (31.75 g, 0.33 moles), which caused the temperature of the solution to rise to 35° C. After cooling the solution to 20° C., 1-tosyl-3-(S)-(−)tosyloxypyrrolidine (126.5 g, 0.3198 moles) was added. The solution was warmed to 70 to 75° C., and, after maintaining the solution at 70 to 75° C. for 4 hours, the reaction was complete. Water (250 ml) and toluene (500 ml) were then added to the solution to form a two phase mixture having an aqueous and an organic phase. The phases were stirred at 70° C. and separated. The aqueous phase was extracted with toluene (50 ml), followed by washing the combined organic phases three times with water (100 ml each), and concentrating under vacuum to give a 250 ml residual volume. The residual volume was cooled to 0° C. to obtain a precipitate. The precipitate was filtered and washed with toluene and water to give the title compound. (Dry weight 116 g, yield 86.5%, and HPLC purity 99.3% area). The main impurities present are residual starting materials: diphenylacetonitrile and N—O-ditosyl-3-(S)-pyrrolidinol in amounts of 0.1% area by HPLC each.

Example 3 Preparation of (S)-2,2-diphenyl-2-(3-pyrrolidinil)acetonitrile hydrobromide (S-DIPACP.HBr) (Formula III)

In a 2 l reactor equipped with mechanical stirrer, thermometer and condenser HBr 48% (1.100 ml), Phenol (44.08 g), and S-DIPACP-N-Tosyl [(S)-2,2-diphenyl-2-(1-tosyl-3-pyrrolidinil)acetonitrile] (220 g) were loaded under nitrogen. The suspension was warmed to reflux (118-120° C.) to obtain a biphasic system. After 1 hr, the reaction was complete (residual starting material 0.33%). The reaction mixture was then cooled to 25-30° C. and dichloromethane (478 ml) was added. After stirring (5 min) the phases were separated (organic phase is upper layer) and the aqueous phase was extracted with dichloromethane (100 ml) and the phases again separated (organic phase is upper layer). The collected organic phases were concentrated to 280-290 ml by solvent distillation at atmospheric pressure to obtain an oily residue (T_(int) 64° C.). Maintaining internal temperature at 65-70° C. ethylacetate (287 ml) was slowly added to the residue. (It is necessary to maintain temperature and to add ethyl acetate slowly to avoid sudden product crystallization). Distillation was continued at atmospheric pressure to reach a volume of 380-390 ml (T_(int) 80° C., T_(head) 70° C.). Ethyl acetate (191 ml) was added to the obtained suspension and distillation was continued at atmospheric pressure to reach a volume of 380-390 ml (T_(int) 84° C., T_(head) 72° C.). Repeated distillations are necessary to eliminate as much dichloromethane as possible in such a way as to increase yield. The suspension was cooled at 50-55° C. and ethyl acetate (300 ml) was added. The suspension was cooled to 20-25° C. and after 1 hr, was cooled to −7-8° C. After 2 hrs, the suspension was filtered and washed three times with cold ethyl acetate (95 ml) each. After washings, the product became white (initially it was pink). The wet product was dried under vacuum at 50-55° C. for 6-7 hrs to obtain the title compound. (Dry weight 166.3 g, yield 87.4%, HPLC purity 99.93% area).

Example 4 (S)-2,2-diphenyl-2-(3-pyrrolidinil)acetonitrile hydrobromide Using β-Naphtol as Bromine Acceptor (Formula III)

(S)-2,2-diphenyl-2-(1-tosyl-3-pyrrolidinil)acetonitrile (5 g, 0.0120 moles) was added to 48% HBr (25 ml) together with β-naphtol (1.73 g, 0.0120 moles), to give a suspension. The suspension was warmed to reflux (117-120° C.), and, after 1 hour the reaction was complete. After cooling to 30° C., dichloromethane (10 ml) was added, and the mixture was stirred for 5 minutes. The phases were separated, and the aqueous phase was extracted with dichloromethane (5 ml). The combined organic phases were washed with saturated solution of NaCl, and then concentrated under vacuum to give a residual volume of 10 ml.

Ethyl acetate (10 ml) was added to the residual volume, and the distillation was continued at atmospheric pressure until a residual volume of 8 ml was obtained. Ethyl acetate was added, and the distillation continued until the dichloromethane was eliminated (residual volume 8 ml). Ethyl acetate (15 ml) and hexane (10 ml) were added to give a suspension. The suspension was cooled to 0° C. for 2 hours to give a precipitate that was filtered and washed with ethyl acetate to give the title compound. (Dry weight 3.0 g; yield 72.4%).

Example 5 Preparation of (S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-acetonitrile hydrobromide (Formula III)

Potassium carbonate (14.94 g, 0.1081 moles) was dissolved in water (45 ml), followed by adding (S)-2,2-diphenyl-2-(3-pyrrolidinil)acetonitrile hydrobromide (18.55 g, 0.0540 moles) and 5-(2-bromoethyl)-2,3-dihydrobenzo[2,3-b]furan (13.5 g, 0.05945 moles) to give a suspension. The suspension was warmed to 75° C., and, after 4 hours, the reaction was considered to be complete (unreacted starting material 1.5% area by HPLC). The heterogeneous mixture was cooled to 25° C. and ethyl acetate (100 ml) was added. After stirring, the phases were separated, the organic layer was washed with water, and the phases separated. 48% hydrobromic acid (9.6 g, 0.05668 moles) was added, and (S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-acetonitrile hydrobromide was crystallized from the suspension. The suspension was cooled to 15-18° C. for one hour, and the precipitate was filtered and washed with ethyl acetate to give the title compound. (Dry weight 23.8 g; yield 89.93%).

Example 6 Preparation of 3-(S)-(−)-(1-carbamoyl-1,1-diphenylmethyl)-1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]pyrrolidine hydrobromide (Formula III)

KOH (1.95 g, 0.03134 moles) was added to 2-methyl-2-butanol (7 ml), to obtain a suspension. The suspension was warmed to 60° C. for 1 hour, followed by adding (S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-acetonitrile hydrobromide (1 g, 0.00204 moles), and warming the reaction mixture (suspension) to reflux for 21-22 hours. After cooling, water (5 ml) was added to the reaction mixture to form a two-phase mixture, and the phases were separated. The solvent was distilled from the organic phase under vacuum, and a residue (0.900 g) was obtained and dissolved in methylethylketone (3 ml). The solution was filtered to eliminate undissolved solid, and 48% HBr (0.344 g, 0.00204 moles) was added. The solvent was distilled under vacuum, and a solid foam was obtained. The foam was slurried in diisopropylether, filtered, and washed to give the title compound. (Dry weight 0.750 g; yield 72%).

Example 7 Preparation of 3-(S)-(+)-(1-carbamoyl-1′-diphenylmethyl)pyrrolidine Tartrate (Formula VI)

3-(S)-(+)-(1-Cyano-1,1-diphenylmethyl)pyrrolidine hydrobromide (80 g 0.2330 moles) was converted into its corresponding free base by treating with dichloromethane (400 ml), water (150 ml) and 30% NaOH (35 g). After phase separation and evaporation of the solvent from the organic phase, an oil residue was obtained. The oil residue was added to 90% H₂SO₄ (130 ml), and the mixture was heated to 100° C. for 17 hours. After cooling, the mixture was neutralized with sulfuric acid until a pH of 12 was obtained. The product was extracted with dichloromethane (250 ml). After washings with water, the solvent was evaporated by distillation, and the product was obtained as a foam (45.7 g). The foam was dissolved in 96% ethanol (460 ml), and L-Tartaric acid (26.9 g) was added, followed by cooling to 0° C., to induce crystallization of the tartrate salt. The salt was filtered after 1 hour, and washed with 96% ethanol to give the title compound. (Dry weight 64.5 g; yield 64.5%).

Example 8 Preparation of 3-(S)-(+)-(1-carbamoyl-1 diphenylmethyl)pyrrolidine Tartrate (Formula VI) a) Free Base Preparation

A four necked round bottomed flask equipped with a thermometer, mechanical stirrer and condenser was charged, under N₂, with 3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine hydrobromide (96 g), Dichloromethane (280 ml), and water (20 ml). The temperature was maintained at 25-30° C. during the loading of NaOH 30% (41.2 g). The obtained heterogeneous system was stirred for 5 min. and the phases were separated. The organic phase was washed with water (41.2 ml), and the phases were separated. The organic phase was concentrated under vacuum until a final volume of 120 ml was obtained.

b) Hydrolysis Reaction

A four necked round bottomed flask equipped with thermometer, mechanical stirrer and condenser to eliminate dichloromethane by distillation, was charged under N₂ with H₂SO₄ 90% (180 ml).

The sulfuric acid solution was warmed to 50-55° C., and the organic solution obtained above (120 ml) was added slowly allowing dichloromethane elimination by distillation. During the addition the mixture was warmed continuously to maintain an internal temperature of 60-65° C. When dichloromethane distillation stopped, the internal temperature was raised to 98-102° C. allowing residual dichloromethane elimination by distillation. Then, the temperature was maintained at 98-102° C. for 14-14.5 hrs.

The reaction mixture was cooled to 25-30° C. and added slowly to a mixture of NaOH 30% (958.3 g), water (720 g), and toluene (480 ml), allowing the internal temperature to reach 55-60° C. After stirring at 55-60° C. the phases were separated at 55-60° C. The aqueous phase was been extracted at 55-60° C. with toluene (160 ml).

The collected organic phases, maintained at 60-65° C., were washed at 60-65° C. with water 240 ml, and then n-butanol (200 ml), water (20 ml) and L-tartaric acid (42.05 g) were added to the separated organic phase at 45-65° C. The mixture was stirred at 45-65° C. until the L-tartaric acid was almost completely dissolved. At the same time a formation of a salt was detected, at the beginning as a white oil, and then as white solid. The suspension was cooled to 15-25° C. and filtered after two hours. When the suspension was too sticky it was found useful to warm to 60-65° C. and after 10-15 min to cool to 15-25° C. and filter. The cake was washed three times with n-butanol (50 ml each), and after 15 hrs of drying at 50-55° C. under vacuum 107 g of the title compound was obtained. (Yield: 88.9%. HPLC purity: 99.88% area).

Example 9 Preparation of 2(2,3-Dihydrobenzofura-5-yl)acetic acid, methyl ester

98% H₂SO₄ (2 g) was added to a solution of 2(2,3-Dihydrobenzofura-5-yl)acetic acid (200 g) in MeOH (500 ml), and the mixture was refluxed for 3 hrs (TLC: SiO₂, toluene/AcOEt 8:2; starting material not detected). After cooling to room temperature, NaHCO₃ (6.7 g) was added to the reaction mixture, and the solvent was distilled off at atmospheric pressure (about 440 ml), to give a light pink oily residue.

The oily residue was dissolved in toluene (250 ml), and washed with NaHCO₃ 6% (50 ml). After the phases were separated, the solvent was eliminated under vacuum distillation to obtain a light pink oily residue (227 g).

Example 10 Preparation of 2(2,3-Dihydrobenzofura-5-yl)ethanol

2(2,3-Dihydrobenzofura-5-yl)acetic acid, methyl ester (227 g residue) was dissolved in t-BuOH (600 ml), and then NaBH₄ (46.8 g) was added. The suspension was warmed to reflux and methanol (100 ml) was added very slowly in about 6 hrs maintaining reaction mixture at reflux. After the methanol addition, the reaction was maintained at reflux for half an hour (In process control revealed complete ester transformation. 400 ml of the t-BuOH-MeOH mixture was distilled off at atmospheric pressure. Water (400 ml) was added to residue and the distillation continued until T_(int)=93° C. and T_(head)=83° C. Water (400 ml) was added, and the distillation continued until T_(int) 96° C. and T_(head)=96° C. The reaction mixture was cooled to 70-75° C. and toluene (300 ml) was added. The separated organic phase was washed with water (100 ml) and NaCl 15% (100 ml). After the solvent was eliminated under vacuum distillation, an oily residue (176.8 g) of the title compound was obtained. The residue solidified upon cooling.

Example 11 2(2,3-Dihydrobenzofuran-5-yl)ethylchloride

SOCl₂ (74.7 g) was added to a solution of 2(2,3-Dihydrobenzofura-5-yl) ethanol 80 g in toluene (400 ml) while maintaining the temperature below 25° C. The reaction mixture was stirred at 60° C. for 14 h and then cooled to room temperature. A reaction sample was quenched into 10% Na₂CO₃ (Residual 2(2,3-Dihydrobenzofura-5-yl) ethanol 0.6% area by HPLC), and the pH was adjusted to 10-11 (measured on aqueous phase) by addition of 10% NaOH (about 480 ml) while maintaining the temperature below 30° C. The organic phase was separated. The aqueous phase was extracted with toluene (50 ml). The collected organic phases were washed twice with H₂O (100 ml each) and anhydrified under vacuum distillation (residual pressure 40-50 mm Hg, T_(int) 50-55° C.). To the organic phase, 20 g of TONSIL® silicate decolorizing agent and 4.2 g of ANTICHROMOS charcoal were added, stirred for 30 min at room temperature, filtered off and washed with toluene (2×30 ml), the decolorized solution was concentrated under vacuum (residual pressure 40-50 mm Hg, T_(int) 50-55° C.) to eliminate toluene. Water (25 ml) was added to obtain a residue, and the residual toluene was eliminated by azeotropic distillation under vacuum (residual pressure 40-50 mm Hg, T_(int) 50-55° C.). This residue was dissolved in methanol (373 ml) and charcoal (2 g) was added. After 20 minutes at 50-55° C. charcoal was filtered off and washed with hot methanol (2×10 ml). The obtained decolorized solution was cooled at 20°-30° C., and 2(2,3-Dihydrobenzofuran-5-yl) ethylchloride crystallized in the suspension. Water (280 ml) was added to the suspension at 25°-30° C. over about 60 min to obtain a sticky, but stirrable, suspension. After 1 hr at 20-25° C. the solid was filtered, and washed three times with MeOH-Water 1:1 (20 ml each). The wet solid was dried at 35-40° C. max for 15 hrs to give the title compound. (Dry weight 81.8 g. Yield 92%. HPLC purity 99.2% area).

Example 12 Preparation of (S)-Darifenacin Hydrobromide

A 50 ml reactor was loaded with —(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate (4 g, 9.29 mmoles), 2(2,3-Dihydrobenzofuran-5-yl) ethylchloride (1.95 g, 10.68 mmoles), potassium carbonate (6.14 g, 44.42 mmoles), and water (12.5 ml), to obtain a heterogeneous mixture. The heterogeneous mixture was heated to reflux (103° C.) for 2.5 hours. After cooling, dichloromethane, EtOAc or BuOAc (15 ml) were added, and, after stirring, the phases were separated. Acetic anhydride (0.5 ml) was added to the organic phase, and, after 1 hour at room temperature, the residual 3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine was transformed into N-Acetyl derivative. The solvent was removed by distillation, and n-butanol (25 ml) was added to the residue. 48% hydrobromic acid (1.72 g) was also added, and the residual DCM was removed under vacuum distillation. In the case of EtOAc or BuOAc, distillation under vacuum is useful to eliminate water. Darifenacin hydrobromide crystallized, and, after cooling to room temperature, the darifenacin hydrobromide was filtered and washed. (Wet solid 4.17 g).

Example 13 Preparation of (S)-Darifenacin Hydrobromide

A 50 ml reactor was loaded with (S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine free base (2.6 g, 9.29 mmoles), 2(2,3-Dihydrobenzofuran-5-yl) ethylchloride (1.95 g, 10.68 mmoles), potassium carbonate (6.14 g, 44.42 mmoles), and water (12.5 ml) to obtain a heterogeneous mixture. The heterogeneous mixture was heated to reflux (103° C.) for 2 to 5 hours. After cooling, dichloromethane, Ethyl acetate, or Butylacetate (15 ml) was added, and, after stirring, the phases were separated. Acetic anhydride (0.5 ml) was added to the organic phase, and, after 1 hour at room temperature, the residual 3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine was transformed into N-Acetyl derivative (as described in example 11). Half of the solvent was removed by distillation, and n-butanol (25 ml) was added to the residue. 48% hydrobromic acid (1.72 g) was also added, and the residual DCM was removed under vacuum distillation. In the case of EtOAC or BuOAc, distillation under vacuum is useful to eliminate water. Darifenacin hydrobromide crystallized, and, after cooling to room temperature, the darifenacin hydrobromide was filtered and washed. (Dry solid 2.5 g).

Example 14 Preparation of (S)-Darifenacin Hydrobromide

A 150 ml reactor was loaded with water (37.5 ml), potassium carbonate (12 g), and 2(2,3-Dihydrobenzofuran-5-yl-ethylchloride (DBF-EtCl) (5.48 g). The mixture was warmed to 60-65° C. and DBF-EtCl melted. Then, (S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate (12 g) was loaded and the heterogeneous mixture was warmed to reflux (101-102° C.) for 5 hrs.

The reaction mixture was cooled to 80-85° C. and n-butanol (60 ml) was added. The internal temperature was maintained at 75-80° C., and the mixture was stirred until complete dissolution was obtained. Then, the mixture was cooled to 25-30° C. and the phases were separated. The organic phase was washed twice with water (30 ml) and the phases were separated.

Water was removed by vacuum distillation until a residual volume of 60 ml was obtained, and then n-butanol (30 ml) was added. Then, acetic anhydride (0.6 ml) was loaded and the mixture was stirred at 20-30° C. for 1 hr, followed by loading HBr 48% (4.7 g) at 25-27° C. The water and 20 ml of butanol were removed by vacuum distillation to obtain a suspension of darifenacin hydrobromide. The suspension was stirred at 25-30° C. for 2 hrs, and then cooled to 0-5° C., and filtered after 1 hr. The cake was washed with cold n-Butanol (3×3 ml), and dried under vacuum at 50-55° C. for 6-7 hrs. (Dry weight 11.2-11.5. Yield 79-81%).

Example 15 Crystallization of (S)-darifenacin hydrobromide

A 100 ml reactor was loaded with crude darifenacin hydrobromide (10 g), n-butanol (70 ml), and charcoal (0.3 g). The mixture was warmed to reflux to obtain a solution. The charcoal was filtered at reflux and washed with n-butanol (5 ml).

The solution was maintained at 100° C. and seeded to induce crystallization. After 30 min at 100° C., the mixture was cooled to 0° C. over 3 hrs, and after 1 hr at 0° C. the mixture was filtered. The product was washed with cold butanol (3×3 ml). (Dry weight 8.8-8.9 g. Yield 88-89%. HPLC purity 99.65-99.75% area).

Example 16 Preparation of (S)-Darifenacin Hydrobromide Via (S)-Darifenamine

3-(S)-(+)-(1-Carbamoyl-1,1-diphenylmethyl)pyrrolidine (2.1 g, 7.5 mmoles) and 2,3-dihydrobenzofuran-5-yl, acetaldehyde (1.4 g, 8.6 mmoles) were combined with toluene (20 ml) at room temperature, and reacted for 15 hours to give (S)-darifenamine.

At this point, a solution of NaBH₄ (0.57 g, 15 mmoles) in ethanol (10 ml) was added slowly, and after 3 hours at room temperature, HPLC analysis revealed formation of (S)-Darifenacin. After washing with water, the solvent was eliminated by distillation, and the obtained residue was dissolved in n-BuOH followed by the addition of HBr 48% (1.5 g, 9 mmoles). Water was eliminated under vacuum, and a slow crystallization was observed. After cooling, the product was filtered and washed with n-BuOH to give the title compound. (Dry weight 0.7 g).

The same reaction has been performed in presence of molecular sieves and titanium isopropylate with similar results.

Example 17 Purification of Darifenacin HBr

The product of Example 16 (3.6 g) was suspended in n-Butanol (25 ml), and heated to reflux to obtain a solution. Charcoal (0.1 g) was added, and, after 5 minutes at reflux, was filtered off. After cooling to room temperature, Darifenacin HBr was filtered, washed, and dried at 45-50° C. under vacuum for 10 hours. (Dry solid 3.20 g; overall yield 68%; HPLC purity 99.86% area).

Example 18 2,3-Dihydrobenzofura-5-yl, acetaldehyde

In a four necked round bottomed flask equipped with thermometer, mechanical stirrer and condenser, was charged under N₂, 2,3-Dihydrobenzofura-5-yl, carboxaldehyde (50 g, 0.33 moles) and 2-butylchloroacetate (66.5 g, 0.4415 moles). The solution was warmed to 40-45° C., followed by a dropwise addition (in about 1 hour) of 288 ml of 17% (w/v) potassium 2-butylate solution in 2-butyl alcohol (0.43 moles). The reaction was maintained at a temperature of 40-45° C., and after 1 hour at 40-45° C., HPLC analysis revealed almost complete transformation of carboxaldehyde. The suspension was slowly added to a solution of KOH 90% (24.5 g, 0.3937 moles) in water (47 ml), followed by maintaining at 45-50° C. After 1 hour at 45° C., TLC analysis revealed complete hydrolysis, and a thick suspension was obtained. At this point toluene (120 ml) and water (180 ml) were added, and the suspension was cooled to 1-5° C. Then, 75% H₃PO₄ (about 50 g) was added drop-wise to obtain a pH in range of 5.4-5.8. During acidification CO₂ evolves and almost complete solid dissolution is observed. After the phases are separated, the organic phase was washed with water (200 ml) and then with sat NaCl, (100 ml). After solvent elimination under vacuum, a residual oil (47 g) of the title compound was obtained.

Example 19 2(2,3-Dihydrobenzofura-5-yl)acetaldehyde, Bisulfitic Complex

In a four necked round bottomed flask equipped with thermometer, and mechanical stirrer, was loaded 2,3-Dihydrobenzofura-5-yl, acetaldehyde, of example 18 (47 g, 0.29 moles) and toluene (500 ml) to obtain a solution. Then, water (100 ml) and Na₂S₂O₅ (58.6 g) were added. The bisulfitic adduct precipitated and after 3 hours at room temperature it was filtered and washed twice with toluene (50 ml each). (Wet product: 95 g).

Example 20 2(2,3-Dihydrobenzofura-5-yl)ethanol

The obtained wet bisulphitic adduct of example 19 was suspended in water (150 ml), and the pH was adjusted to 10-10.2 with NaOH 30%. Na₂CO₃ 10% (50 ml) and toluene (100 ml) were added and, after cooling to 5-10° C., a solution of NaBH₄ (5.8 g, 0.1526 moles)) in water (40 ml) was added drop-wise over about 45-60 minutes, while maintaining the pH at 9.8-10.2. The temperature was raised to 15-20° C. and after 1 hour the phases were separated. The aqueous phase was extracted with toluene (25 ml), and the combined organic phases were washed with water (50 ml). The solvent was eliminated under vacuum distillation, and the obtained oil solidified to give the title compound (26 g).

Example 21 Preparing 5-(2-chloroethyl)-2,3-dihydrobenzofuran of Formula II in DMF, Toluene and in a Mixture of Dimethylformamide (DMF) and Toluene

Level of 2- Level of 5-(2- (benzofuran-5- chloroethyl)-2,3- Temperature yl)ethanol of formula benzofuran of formula Solvent (° C.) V (area % by HPLC) I (area % by HPLC) DMF 20° C. nd 0.3 DMF 0-5° C. ndv 0.44 Toluene/ 55° C. 0.01 1.15 DMF 99:1 Toluene 60° C. 0.03 0.21 Toluene 60° C. nd 0.19 Toluene 60° C. nd 0.14 * nd = not determined

Example 22 Correlation Between the Levels of the Oxidized Impurities in the Intermediates for Preparing Darifenacin Hydrobromide to the Level of Oxidized Darifenacin

Level of Level of Level of Level of Level of impurity impurity impurity impurity impurity (w/w (area % by (area (area % (area % % by HPLC) HPLC) % by HPLC) by HPLC) by HPLC) Oxidized BF—AcOH BF—AcOMe BF-EtOH BF-EtCl darifenacin 0.18 0.17 0.16 0.18 0.09 0.50 0.53 0.47 0.30 0.49 *BF—AcOH is benzofuran-5-acetic acid; BF—AcOMe is benzofuran-5-methylester acetic acid; BF-EtOH is benzofuran-ethanol; and BF-EtCl is 5-(2-chloroethyl)-benzofuran.

Comparative Example 23 Example 1 from U.S. Pat. No. 5,096,890 (col. 6, 1.56 to col. 7, 1.51) (A) Preparation of 3-(R,S)-(1-carbamoyl-1,1-diphenylmethyl)-1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]pyrrolidine

A mixture containing 3-(R,S)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine (0.33 g—see Preparation 8), 5-(2-bromoethyl)-2,3-dihydrobenzofuran (0.25 g—see Preparation 13), anhydrous potassium carbonate (0.3 g) and acetonitrile (10 ml) was heated under reflux for 2 hours. The mixture was partitioned between dichloromethane (50 ml) and 10% aqueous potassium carbonate (10 ml), the layers were separated, and the aqueous layer extracted with dichloromethane (3×20 ml). The combined dichloromethane extracts were dried (MgSO₄) and concentrated in vacuo to leave a gum which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 8%). The product-containing fractions were combined and concentrated in vacuo to leave an oil which was crystallised from diisopropyl ether to give the title compound as a colourless powder, yield 0.17 g, m.p. 131°-132° C.

Analysis %. Found: C, 78.90; H, 7.70; N, 6.28. Calculated for C₂₈H₃₀N₂O₂: C, 78.84; H, 7.90; N, 6.57.

¹H N.m.r. (CDCl₃) δ=7.50-7.20 (m, 11H); 7.00 (s, 1H); 6.90 (d, 1H); 6.70 (d, 1H); 5.45-5.30 (brs, 1H); 4.60-4.50 (t, 2H); 3.60-3.45 (m, 1H); 3.25-3.15 (t, 2H); 3.05-2.50 (m, 8H); 2.10-1.95 (m, 2H) ppm.

(B) A similar procedure starting with 3-(S)-(−)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine (1.95 g—see Preparation 10(B)) gave 3-(S)-(−)-(1-carbamoyl-1,1-diphenylmethyl)-1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]pyrrolidine as a foam, yield 1.9 g, [α]_(D) ²⁵ −20.6° (c 1.0, CH₂Cl₂).

(C) A similar procedure starting with 3-(R)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine (2.8 g—see Preparation 11) gave 3-(R)-(+)-(1-carbamoyl-1,1-diphenylmethyl)-1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]pyrrolidine as a foam, yield 1.7 g, [α]_(D) ²⁵ +18.1 (c 1.0, CH₂Cl₂).

While it is apparent that the invention disclosed herein is well calculated to fulfill the objects stated above, it will be appreciated that numerous modifications and embodiments may be devised by those skilled in the art. Therefore, it is intended that the appended claims cover all such modifications and embodiments as falling within the true spirit and scope of the present invention. 

1. N-protected-3-(S)-pyrrolidinol of the formula,

wherein X is S, SO₂, Si, or CO, and R is phenyl, tolyl, ortho, meta, or para-xylyl, linear or branched C₁₋₁₀ alkyl, H, or CF₃.
 2. The N-protected-3-(S)-pyrrolidinol of claim 1, wherein X is S and R is phenyl.
 3. The N-protected-3-(S)-pyrrolidinol of claim 1, wherein X is S and R is tolyl.
 4. The N-protected-3-(S)-pyrrolidinol of claim 3, having a melting temperature of about 108° C. to about 112° C.
 5. The N-protected-3-(S)-pyrrolidinol of claim 1, wherein X is S and R is xylyl.
 6. The N-protected-3-(S)-pyrrolidinol of claim 1, wherein X is S and R is linear or branched C₁₋₁₀ alkyl.
 7. The N-protected-3-(S)-pyrrolidinol of claim 1, wherein X is SO₂ and R is phenyl.
 8. The N-protected-3-(S)-pyrrolidinol of claim 1, wherein X is SO₂ and R is tolyl.
 9. The N-protected-3-(S)-pyrrolidinol of claim 1, wherein X is SO₂ and R is xylyl.
 10. The N-protected-3-(S)-pyrrolidinol of claim 1, wherein X is SO₂ and R is linear or branched C₁₋₁₀ alkyl.
 11. The N-protected-3-(S)-pyrrolidinol of claim 1, wherein X is Si and R is linear or branched C₁₋₁₀ alkyl.
 12. The N-protected-3-(S)-pyrrolidinol of claim 1, wherein X is CO and R is H.
 13. The N-protected-3-(S)-pyrrolidinol of claim 1, wherein X is CO and R is CF₃.
 14. The N-protected-3-(S)-pyrrolidinol of claim 1, wherein X is CO and R is CH₃. 